Biopharmaceuticals are generally administered through venous, intramuscular or subcutaneous injections (e.g., parenteral drug delivery). Oral delivery is not typically used because often proteins are adversely affected by or poorly absorbed (due to their large size and instability) through the gastrointestinal tract. Thus, many new biotechnology drugs, including those used for the treatment of cancer, are formulated and produced using the freeze-drying process. Freeze drying (e.g., lyophilization) produces stable drug products that can be stored and reconstituted for patient use. Although drying stabilizes the active pharmaceutical ingredient for long term storage, freeze-drying exposes proteins to numerous in-process degradation processes that can have adverse effects on the drug efficacy. To prevent these degradation processes, pharmaceutical companies produce drug specific formulations and use freeze-drying processes that ensure that the final product has a high level of purity and has a targeted two-year shelf life.
The development of biological drugs often requires product formulations that must be lyophilized to produce stable products, which can be stored in vials and reconstituted for patient use. Lyophilization is the process of drying (e.g., removing water from) a pharmaceutical compound by freezing it first and then sublimating the ice. An important process design parameter is the product temperature during primary drying which is typically set at or below the temperature at which the product undergoes structural collapse during primary drying (e.g., the collapse temperature (“Tc”)). Tc is the temperature at which the amorphous pharmaceutical formulation being dried undergoes viscous flow resulting in structural collapse. When the product formulation is frozen during the freeze drying process, pores form, which cause the ice formation to appear to have a sponge or cake-like structure. During the primary drying phase of the freeze drying process, as the product temperature approaches Tc, viscous flow within the product structure can occur with the pores getting larger. There are different levels of structural change, which include micro-collapse (which can be tolerated) and complete collapse. During the lyophilization of pharmaceutical products manufacturers seek to avoid collapse to ensure elegant appearance of the freeze dried cake, low residual water content, storage stability and positive reconstitution characteristics.
Current light transmission based freeze drying microscopy (“LT-FDM”) systems are limited to estimating Tc using 1-2 μL, liquid product samples frozen between microscope slides, resulting in a frozen product thickness of 50-100 μm. These samples do not always provide accurate collapse temperature determinations due to differences in ice nucleation rates, crystallization tendencies for solutes, frozen product structures and drying rates as compared to samples prepared and freeze dried in vials. Furthermore, LT-FDM samples are not representative of samples dried in vials, which can have thicknesses of 5-50 mm.
Thus, current LT-FDM techniques do not accurately estimate Tc for freeze drying in a container of practical significance. Literature studies suggest that the differences in Tc between current FDM and vial drying are typically several degrees, which results in a 25% increase in primary drying time for every 2° C. decrease in product processing temperature. A 25% increase in time can significantly impact the economic viability of a process that can require 1-4 days under ideal processing conditions, without the increase in time due to overly conservative process conditions used due to a lack of knowledge of the product formulation collapse temperature.